Delta2-1,2,3-triazoline anticonvulsants and their active metabolite analogues, the aminoalkylpyridines, are excitatory amino acid antagonists and antiischemic agents, useful in the treatment of cerebral ischemia resulting from stroke

ABSTRACT

Pharmaceutical compositions comprise as the active ingredient, nonneurotixic antiischemic compounds that are highly effective by the intraperitoneal route, and that are excitatory amino acid and NMDA/sigma receptor antagonists and are selected from the group consisting of those of the formulae,  
                 
 
     wherein R 2  is 4-pyridyl, 3-pyridyl, or 2-oxo- 1 -pyrrolidino and R 1  is 3,4- or 3,5-dichloro, p- or m-chloro, p- or m-bromo, p- or m-fluoro, p- or m-trifluoromethyl, p-methyl, p-methoxy, or hydrogen, and those of the formulae,  
                 
 
     wherein R 2  is 4-pyridyl or 3-pyridyl, R 3  is hydrogen, methyl or ethyl and R 1  is 3,4- or 3,5-dichloro, p- or m-chloro, p- or m-bromo, p- or m-fluoro, p- or m-trifluoromethyl, p-methyl, p-methoxy or hydrogen.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority from Provisional ApplicationSerial No. 60/244,930, filed Nov. 2, 2000, and Provisional ApplicationSerial No. 60/307,360, filed Jul. 25, 2001, the disclosures of theseprovisional applications being incorporated herein by reference.

FIELD OF THE INVENTION

[0002] This invention relates to the drug potential of anticonvulsantsin the treatment of stroke, particularly, several Δ²-1,2,3-triazolineand aminoalkylpyridine (AAP) anticonvulsants that seem to work byimpairing the excitatory amino acid (EAA) L-glutamate (L-Glu)neurotransmission, as antiischemic agents, useful in the treatment ofstroke victims.

[0003] There is strong evidence that the “excitotoxic” action resultingfrom the excessive accumulation of L-Glu plays a prominent role in humanepilepsy as well as brain ischemia/stroke, leading to neuronaldysfunction and cell death. The 1,2,3-triazolines and theaminoalkylpyridine (AAP) metabolite analogues are two groups of novelanticonvulsants discovered in the Applicant's laboratories. These arevery effective in the kindling and in the maximal electroshock (MES)seizure models of epilepsy, the best analogies to human partialseizures, where EAA neurotransmission plays an important role. Thus itis logical to expect that the anticonvulsant triazolines and AAPmetabolite analogues would evince beneficial therapeutic potential incerebral ischemia.

[0004] The ability of the triazolines and AAP compounds to affordprotection and reduce neuronal degeneration are assessed in animalmodels of stroke, by utilizing the bilateral carotid occlusion model inthe gerbil and the middle cerebral artery occlusion (MCAO) model in therat. Post-ischemic gerbils undergo a predictable pattern of behavioralchanges and the effects of drugs in producing alterations in thispattern are monitored by determining the post ischemic changes inlocomotor activity as well as by changes in radial arm maze performance,and corroborated by post reperfusion histopathological assessment. Inthe MCAO rat model, a focal stroke model, drug effects are evaluatedfrom their ability to reduce the infarct volume following MCAO.

BACKGROUND ART

[0005] There is a desperate need for clinically effectivechemotherapeutic agents for intervention in and management of cerebralischemia resulting from stroke. In the U.S. alone, 1.1 millionindividuals suffer stroke annually; it is the most common, anddevastating neurological condition that kills more than a quartermillion Americans every year and the leading cause of long-termintellectual and physical disability. In the past decade, it has becomeincreasingly evident from data from numerous laboratories that EAAneurotransmission plays an important role in ischemic brain injuryoccurring in stroke and other neurological disorders (McCulloch, J., etal., Ed., “Frontiers in Pharmacology and Therapeutics: Excitatory AminoAcid Antagonists.”, Oxford, UK; Blackwell Scientific Publishers,287-326, 1991: Choi, D. W. & Rothman, S. M., Annu. Revs., Neurosci., 13,171-182, 1991; Takagi, K., et al., J. Cereb. Blood Flow Metab., 13,575-585, 1993; Graham, S. H., et al., J. Cereb. Blood Flow Metab., 13,88-97, 1993; Muir, K. W., & Lees, K. R., Stroke, 26, 503-515, 1995). Theexcessive accumulation of the excitatory neurotransmitter L-Glu,followed by its excitotoxic action, has been strongly implicated in thecascade of pathological mechanisms that cause neuronal dysfunction andcell death in cerebral hypoxia-ischemia resulting from stroke, cardiacarrest, or mechanical brain injury. Thus, the EAA neurotransmittersystems may be considered potential therapeutic targets and developmentof agents that are EAA antagonists may constitute novel and effectivetherapies, as cytoprotective agents, in stroke.

SUMMARY OF THE INVENTION

[0006] It is accordingly one object of the present invention to providenovel Δ²-1,2,3-triazolines and AAP compounds and their method ofpreparation.

[0007] It is a further object of the present invention to provideantiischemic/antistroke agents which comprise triazolines and AAPcompounds

[0008] A further object of the present invention is to provide a methodfor the treatment of cerebral ischemia resulting from stroke, byadministration of an effective amount of the triazoline and AAPcompounds of this invention.

[0009] A further object of the present invention is to providetriazolines and AAPs bearing three different pyridyl substituents and apyrrolidinone group, and methods for their use in the treatment ofneurological disorders such as cerebral ischemia resulting from strokeand also in the treatment of epilepsy.

[0010] A still further object of the present invention is to providetriazolines and AAP compounds, as inhibitors of the EAA neurotransmitterL-glutamate. The triazolines and AAPs of this invention affordpronounced protection in the maximal electroshock seizure (MES) model inboth mice and rats, by the intraperitoneal, intravenous, and oral route,which is indicative of their action as glutamate antagonists.

[0011] A still further object of the present invention is to provideantiischemic compositions that contain as the essential ingredientcertain triazolines and AAPs and that are highly effective by theintraperitoneal and intravenous routes, the preferred routes ofadministration, in stroke victims, and use of these triazolines and AAPsas effective antiischemic drugs in the treatment of cerebral ischemiaresulting from stroke.

[0012] Other objects and advantages of the present invention include useof the triazolines and AAPs in the treatment of stroke and epilepsy andalso other neurological disorders such as Parkinson's disease, by virtueof their action as EAA antagonists and inhibitors of L-glutamateneurotransmission.

[0013] In satisfaction of the foregoing objects and advantages, thereare provided by this invention several triazolines and AAPs which areuseful as antiischemic/antistroke drugs. The various groups oftriazolines and AAPs substituted with the various pyridyl groups andalso the pyrrolidinyl group, may be characterized by the followinggeneral formulae:

[0014] [1-(Phenyl)-5-(4-pyridyl)-Δ²-1,2,3-triazolines]

[0015] [1-(Phenyl)-5-(3-pyridyl)-Δ²-1,2,3-triazolines]

[0016] [1-(Phenyl)-5-(2-pyridyl)-Δ²-1,2,3-triazolines]

[0017] [1-(Phenyl)-5-(2-oxo-1-pyrrolidino)-Δ²-1,2,3-triazolines]

[0018] [1-(N-Phenyl)-1-(4-pyridyl)-1-ethylamine] (propyl)

[0019] [1-(N-Phenyl)-1-(2-pyridyl)-1-ethylamine] (propyl)

[0020] [1-(N-Phenyl)-1-(2-pyridyl)-1-ethylamine] (propyl)

[0021] wherein R¹ is 3,4- or 3,5-dichloro, p- or m-chloro, p- orm-bromo, p- or m-fluoro, p- or m-trifluoromethyl, p- or m-lower alkyl,p- or m-lower alkoxy or hydrogen.

[0022] Also provided by this invention are non-toxic antiischemiccompositions that are intraperitoneally and intravenously active andcomprise as the active ingredient, a compound selected from those of theformulae (I-VII), wherein R¹ is 3,4- or 3,5-dichloro, p- or m-chloro, p-or m-bromo, p- or m-fluoro, p- or m-trifluoromethyl, p- or m-loweralkyl, p- or m-lower alkoxy or hydrogen.

[0023] Also provided are methods for the administration of theantiischemic compositions of this invention to mammals, includinganimals and humans, in the treatment of cerebral ischemia resulting fromstroke, including both global ischemia and focal ischemia.

DESCRIPTION OF PREFERRED EMBODIMENTS

[0024] As indicated above, this invention relates to several groups ofcompounds belonging to the seven structures (I-VII) shown above, whichare useful as antiischemic drugs in the treatment of cerebral ischemiaresulting from stroke. In one group of triazolines (I) and AAPs (V), a4-pyridyl substituent is present, in a second group of these compounds(II & VI), a 3-pyridyl substituent and in a third group (III & VII), a2-pyridyl substituent is present. Also, in a fourth group of triazolines(IV), a 2-oxo-1-pyrrolidino group is present. In all three groups of AAPcompounds, the R² group is methyl, ethyl or phenyl. The triazolines andAAPs of this invention are further substituted on the phenyl rings by3,4- or 3,5-dichloro, p- or m-chloro, p- or m-bromo, p- or m-fluoro, p-or m-trifluoromethyl, p- or m-lower alkyl, p- or m-lower alkoxy orhydrogen. The triazolines and AAPs of this invention have potentantiischemic activity and protect the brain from neuronal damage in bothglobal and focal ischemia, and are useful as antiischemic/antistrokedrugs in the treatment of cerebral ischemia resulting from stroke inhumans.

[0025] In one aspect of the present invention, three groups oftriazolines and two groups of AAPs, are provided which have potentantiischemic activity and which have the general formulae represented bystructures I, II and IV, and V and VI, respectively. In the aboveformulae, in structures I and II, the 5-substituent is 4-pyridyl or3-pyridyl and R¹ is 3,4- or 3,5-dichloro, p- or m-chloro, p- or m-bromo,p- or m-fluoro, p- or m-trifluoromethyl, p- or m-lower alkyl, p- orm-lower alkoxy or hydrogen. In structure IV, the 5-substituent is a2-oxo-1-pyrrolidino group and R¹ is 3,4- or 3,5-dichloro, p- orm-chloro, p- or m-bromo, p- or m-fluoro, p- or m-trifluoromethyl, p- orm-lower alkyl, p- or m-lower alkoxy or hydrogen. Structures V and VI,are 4-pyridyl and 3-pyridyl AAPs respectively, where R⁴ is methyl, ethylor phenyl and R¹ is 3,4- or 3,5-dichloro, p- or m-chloro, p- or m-bromo,p- or m-fluoro, p- or m-trifluoromethyl, p- or m-lower alkyl, p- orm-lower alkoxy, or hydrogen. Several of these triazolines and AAPcompounds are potent anticonvulsants and are already under U.S. patentprotection (P. K. Kadaba, U.S. Pat. No. 4,511,572, 1985; U.S. Pat. No.4,689,334, 1987; U.S. Pat. No. 4,820,721, 1989; U.S. Pat. No. 5,648,369,1997; U.S. Pat. No. 6,083,964, 2000).

[0026] In a second aspect of this invention, there are provided novelantiischemic compositions which are effective by the intraperitoneal andintravenous routes and are non-toxic, and which comprise as the activeingredient an effective amount of a compound selected from those of theseven groups represented by structures (I-VII), and having 4- or3-pyridyl, or 2-oxo-1-pyrrolidinyl substituent groups, and R⁴ and R¹ areas described above.

[0027] There are further provided by this invention, methods for theadministration of the antiischemic compositions to mammals includinganimals and humans.

[0028] In a third aspect of this invention, there are providedtriazoline and AAP compounds of the formulae represented by thestructures (I-VII), and which exhibit pronounced and selective activityin the MES test and the kindling model of epilepsy, and are useful inthe treatment of stroke.

[0029] Significance of Pronounced Selective Activity in the MES Test:

[0030] Both the triazolines and the AAP compounds of this inventionexhibit pronounced and selective anticonvulsant activity in the maximalelectroshock seizure (MES) test. While the triazolines show activity inthe subcutaneous Metrazole (scMet) test also, the AAPs show hardly anyactivity in the scMet test. The activity of the compounds of thisinvention in the MES test is of great significance, because partialseizures in humans correlate positively with experimental seizureselicited by the MES test [Porter, R. J. and Pitlick, W. H., In “Basicand Clinical Pharmacology”, 4th Edn., B. G. Katzung Ed., Appleton &Lange, C. A., 1989, pp 287-303]. Since antiepileptic drugs effectiveagainst MES seizures alter ionic transport across excitable membranes,the triazolines and the AAPs that evince significant activity in the MEStest, may be expected to attenuate EAA neurotransmission. There isstrong evidence that the excitatory neurotransmitter glutamate plays akey role in EAA neurotransmission along limbic circuits which areparticularly relevant to kindling epileptogenesis. Since the triazolinesand the AAPs are quite effective in the kindling model, both theseclasses of compounds could be expected to be effective glutamateantagonists.

[0031] 1,2,3-Triazoline and AAP Anticonvulsants, and Their Mechanism ofAnticonvulsant Activity, as Inhibitors of Both Post- and Presynaptic EAANeurotransmission:

[0032] Previous studies in our laboratories had led to the emergence ofthe 1,2,3-triazoline heterocycles represented by structures I-IV, as anew class of anticonvulsant agents with a unique mechanism of actionquite different from the more traditional anticonvulsants (Kadaba, P.K., J. Med. Chem., 31, 196-302, 1988; “Drugs of the Future”, 15,1013-1024, 1990; Kadaba, P. K., and Slevin, J. T., Epilepsia, 29, 330,1988; Kadaba, P. K., and Slevin, J. T., Pharmaceut. Res., 6, S-42, 1989;Kadaba, P. K. and Slevin, J. T., 200th Nat. Meeting of the ACS,Washington, D.C., Abstracts, 56, MEDI 31, 1990; Kadaba, P. K.,Stevenson, P. J., Nnane, I. P., and Damani, L. A., Bioorg. Med. Chem.,4, 165-178, 1996). The triazolines afford a high degree of protection inseizure provocation by chemical (scMet) and electrical (MES) stimuli andhave good protective indices. They offer complete protection againstN-methyl D-aspartate (NMDA)-induced seizures in the mouse atsignificantly low ED₅₀ values: (Kadaba, P. K., et al., Bioorg. Med.Chem., 4, 165-178, 1996). They show good response on oral administrationand a good margin of safety. They compare very well with prototypeantiepileptic drugs in both mice and rats. Unlike the prototype drugs,one triazoline represented by structure 1, R¹=p-Cl, offers completeprotection against stimulus-induced electrographic after-dischargeseizures and generalized convulsions, in both amygdala-kindled(ED₅₀=215±61 mg/kg) and entorhinal-kindled rats (ED₅₀=423±45 mg/kg), innon-sedative, non-neurotoxic doses (Kadaba, P. K., “Drugs of theFuture”, 15, 1013-1024, 1990; Kadaba, P. K. & Slevin, J. T., Pharmaceut.Res., 6, S-42, 1989).

[0033] Studies on the metabolism and in vivo and in vitro pharmacologyof triazolines represented by structure I and potential metabolites,seem to indicate that the triazolines may be functioning as prodrugs andact by a unique “dual-action” mechanism; while the parent triazolineinhibits the presynaptic release of glutamate (58% at 50 μM and 83% at100 μM drug concentration), the active β-amino alcohol metabolitedisplaces >90% of the binding of [³H]-Glu from glutamate receptors, and56% of the binding of [³H]MK-801, from the MK-801 sites on the NMDAreceptor ionophore complex (Kadaba, P. K., ACS Abstrs. MEDI 144, 1991;Kadaba, P. K. & Slevin, J. T., Epilepsia, 29, 330, 1988; Pharmaceut.Res., 6, S-42, 1989; ACS Abstrs., 56, MEDI 31, 1990; Kadaba, P. K., etal., Bioorg. Med. Chem. 4, 165-178, 1996). Furthermore, radioligandbinding studies at ion-channel binding sites using [³H]TBOB, indicatessignificant activity at Cl⁻ channels ranging from 50 to 63% at 10 μMconcentration, for triazolines belonging to structure I (Kadaba, P. K.,et al., Bioorg. Med. Chem. 4, 165-178, 1996). Augmentation in Cl⁻ influxis a useful membrane action that reduces membrane excitability or alterscircuit behavior to favor inhibition, and thus might help suppress thefiring of glutamatergic neurons and hence glutamate release. Such drugsmay be most beneficial in the control of prolonged seizures such as instatus epilepticus where excessive neuronal firing occurs (Choi, D. W.,Cerebrovasc. Brain Metab. Revs., 2, 105-147, 1990). And indeed, thecomplete protection afforded by triazoline I (R¹=p-Cl) against amygdala-and entorhinal-kindled seizures as well as NMDA-induced convulsions issignificant, in view of the current concepts regarding the central roleof EAA neurotransmission, particularly L-Glu, in the kindling model ofhuman partial epilepsy.

[0034] Studies by the Applicant on the metabolism and pharmacology ofthe triazoline anticonvulsants have led to the evolution and discoveryof the aminoalkylpyridines (AAPs) as a unique class of orally activeanticonvulsant agents, superior to the triazolines themselves (Kadaba P.K., et al. Bioorg. Med. Chem., 2, 165-178, 1996; Kadaba, P. K., U.S.Pat. No. 4,511,572, 1985; U.S. Pat. No. 4,618,681, 1986; U.S. Pat. No.4,689,334, 1987; U.S. Pat. No. 4,820,721, 1981). Work on theaminoalkylpyridines indicate they are non-toxic, and highly effective bythe oral route, with protective indices greater than 20. The AAPs alsoshow high anticonvulsant activity in the MES test and are practicallyinactive in the scMet test (Deshmukh, T. R. & Kadaba, P. K., Med. Chem.Res., 3, 223-232, 1993; U.S. Pat. No. 5,648,369,1997).

[0035] Radioligand binding and release studies indicate that the abilityof triazolines to impair presynaptic release of glutamate is retained tothe full extent or better in the corresponding AAP compounds (V,R¹=p-Cl) (74% at 50 μM and 80% at 100 μM drug concentration as also thepostsynaptic activity of the 13-amino alcohol, albeit at a differentsite; the AAP compounds weakly displace [³H]DTG, a o specific ligand,with Ki values in the μM range and show no affinity for the PCP sites(Kadaba, P. K., ACS Abstrs. MEDI 073, 1992; Pharmaceut. Res., MNPC 5013,11, S-120, 1994a; Epilepsia, AES, Dec. 5, 1994b; Deshmukh, T. R., &Kadaba, P. K., J. Pharm. Res. 9, S-109, 1992; Med. Chem, Res. 3, 323,1993; Kadaba, P. K., & Deshmukh, T. R., ACS Abstrs., MEDI, 1069, 1993a;Amino Acios, June, 1993b; Kadaba, P. K., et al., Bioorg. Med. Chem., 2,165-178, 1996). As o and PCP sites are two distinct molecular entities(Kamenka, J. M. & Domino, E. F., (Eds), “Multiple Sigma and PCP ReceptorLigands: Mechanisms for Neuromodulation and Neuroprotection?”, NPPBooks, P.O. Box 1491, Ann Arbor, Mich., 48106, 1992) and the o receptoris not a component of the NMDA receptor-ionophore complex, the potentanticonvulsant activity of the AAPs seems to result from their selectivelow-affinity interaction at o₁ sites. The selectivity of the AAPs forthe o receptor sites with no activity at the PCP sites, might alsoaccount for the absence of undesirable toxic side effects in thesecompounds.

[0036] EAA Neurotransmitter Systems and the NMDA Receptor Complex inRelation to Epilepsy and Cerebral Ischemia:

[0037] The role of EAAs and the NMDA receptor in health and disease areextensively reviewed (Cavalheiro, E. A., Lehmann, J., and Turski, L.,Eds., “Frontiers in Excitatory Amino Acid Research”, A. R. Liss, NewYork, N. Y., 1988; Cotman, C. W., Bridges, R. J., Taube, J. S., Clark,A. S., Geddes, J. W., and Monaghan, D. T., J.NIH Res., 1, 65, 1989;Dingledine, R., Boland, L. M., Chamberlin, N. L., Kawasaki, K.,Kleckner, N. W., Traynelis, S. F., and Verdoom, T. A., CRC Crit. Rev.Neurobiol., 4, 1, 1988; Honore, T., Med Res. Rev. 9, 1, 1989; Johnson,G., Ann. Rep. Med. Chem., 24, 41, 1989). Overstimulation of the NMDAreceptor by high levels of glutamate has been implicated in bothepilepsy (Cavalheiro, E. A., Lehmann, J., and Turski, L., Eds.,“Frontiers in Excitatory Amino Acid Research”, A. R. Liss, New York,N.Y., 1988; Fisher, R. S. and Coyle, J. T., Eds., “Neurotransmitters andEpilepsy”, Wiley-Liss, New York, N.Y., 1991) and stroke (Meldrum, B. S.and Garthwaite, J., TIPS, 11, 379-385, 1990; Rothman, S. M. and Olney,J. W., Ann. Neurol., 19, 105-111, 1986). Both diseases have beensuggested to have a common pathology, i.e., chronic or acute cell deathresulting from EAA-induced “excitotoxicity” (Greenamyre, J. T., Maragos,W. F., Albin, R. L., Penny, J. B., and Young, A. B., Prog. NeuroPsychopharmacol & Biol. Psychiat., 12, 421, 1988; Mayer, M. L., andWestbrook, G. L., Prog. Neurobiol., 28, 197, 1987; Choi, D. S., Neuron,1, 623, 1988; Simpson, M. D. C., Royston, M. C., Deakin, J. F. W.,Cross, A. J., Mann, D. M. A., and Slater, P., Brain Res., 462, 76,1988). Excessive accumulation of glutamate leads to overactivation ofthe NMDA receptor resulting in excessive intraneuronal Ca²⁺ whichprecipitates neurodegeneration and neuronal death (Cotman, C. W.,Bridges, R. J., Taube, J. S., Clark, A. S., Geddes, J. W., and Monaghan,D. T., J. NIH Res., 1, 65, 1989). Evidence for the excitotoxic action ofglutamate at the NMDA receptor, derived from numerous studies ofcultured cortical neurons in vitro (Choi, D. S. Neuron, 1, 623, 1988),suggests an influx of Ca²⁺ through the stimulated NMDA ionophore to be aprerequisite for cell death to occur (Choi, D. S., Neuron, 1, 623, 1988;Hahn, J. S., Aizenman, E., and Lipton, S. A., Proc. Natl. Acad. Sci.,85, 6556, 1988; Ogura, A., Miyamoto, M. and Kudo, Y., Exp. Brain Res.73, 447, 1988). Agents that block the action of glutamate and thus theoverstimulation of the NMDA receptor thus represent novel therapies, asneuroprotective agents, for both epilepsy and cerebral ischemiaresulting from stroke (Johnson, G., Ann. Rep. Med. Chem., 24, 41, 1989;Cotman, C. W., Bridges, R. J., Taube, J. S., Clark, A. S., Geddes, J.W., and Monaghan, D. T., J. NIH Res., 1, 65, 1989). Thus, based on theability of the triazoline and the AAP anticonvulsants to effectivelyimpair glutamate neurotransmission, it appears logical to expect thatthese compounds would provide beneficial drug candidates forstroke-related ischemic brain damage.

[0038] EAAs and the Kindling Model of Epilepsy:

[0039] The kindling phenomenon mimics human epilepsy (Kalichman, M. W.,Neurosci. Biobehav. Rev., 6, 165, 1982) and there is increasing evidencethat EAAs may play an important role in kindling mechanisms. EAAs may becritically involved in both epileptogenesis and as a focus for themechanism of action of anticonvulsants (Meldrum, B. S., and Chapman, A.G., In “Glutamine, Glutamate, and GABA in the Central Nervous System,”,L. Hertz, et al., Ed., Alan R. Liss, Inc., New York, 1983, pp 625-641;Cavalheiro, E. A., Lehmann, J., and Turski, L., Eds., “Frontiers inExcitatory Amino Acid Research”, A. R. Liss, New York, N.Y., 1988; Muir,K. W. and Lees, K. R., Stroke, 26, 503-513, 1995). Enhanced activity atthe EAA synapse will lower the threshold and promote hyperactivity ofthe postsynaptic neuron. Evidence for a causal connection between EAArelease and onset of hyperactivity has been provided by the use ofspecific EAA receptor antagonists, APB, APV, and APH, in various modelsof epilepsy (Cruczwar, S. J., and Meldrum, B. S., Eur. J. Pharmacol.,83, 335, 1982).

[0040] EAAs and Cerebral Ischemia:

[0041] Brain regions such as the hippocampus and the dorsolateralstriatum that are enriched in EAA receptors are especially vulnerable toischemic lesions (Jorgensen, M. D. and Diemer, N. A., Acta Neurol.Scand., 66, 536-46, 1982) and selective brain lesioning studies havesupported a role for glutamate in ischemic and hypoglycemic brain injury(Jorgensen, M. B., Johnson, F. F., and Diemer, N. H., Acta Neuropathol.,73, 189, 1987; Linden, T., Kalimo, H., and Weiloch, T., ActaNeuropathol., 74, 335, 1988). Furthermore, ischemia-induced hippocampaldamage is reduced by prior local infusion of EAA receptor antagonists(Simon, R. P., Griffiths, T., Evans, M. C., Swan, J. H., and Meldrum, B.S., J. Cereb. Blood Flow Metab., 4, 350-361, 1984; Simon, R. P., Swan,J. H., Griffiths, T., and Meldrum, B. S., Science, 226, 850-852, 1984)or by their systemic administration (Boast, C. A., Gerhardt, S. C.,Pastor, G., Lehmann, J., Etienne, P. E., and Liebman, J. M., Brain Res.,442, 345-348, 1988). Glutamate can trigger toxic neuronal degenerationwith considerable potency and speed; a 5-minute exposure to 100 μM Gluis sufficient to destroy large numbers of cultured cortical neurons(Choi, D. W., Maulucci-Gedde, M. A., Kriegstein, A. R., L Neurosci., 7,357-368, 1987). Such brief intense exposure likely accompanies severaltypes of acute insults, including hypoxia (Rothman, S. M., J. Neurosci.,4, 188-191, 1984), ischemia (Simon, R. P., Griffiths, T., Evans, M. C.,Swan, J. H., and Meldrum, B. S., J. Cereb. Blood Flow Metab., 4,350-361, 1984; Simon, R. P., Swan, J. H., Griffiths, T., and Meldrum, B.S., Science, 226, 850-852, 1984) and prolonged seizures (Ben-Ari, Y.,Neuroscience, 14, 375-403, 1985).

[0042] In the hippocampus, the pattern of neuronal loss is similar afteran episode of ischemia or of status epilepticus or temporal lobeepilepsy, the most common form of focal (partial) epilepsy. Irreversiblecell loss is common in the hilus of the hippocampal area dentata and inthe CA1 and CA3 pyramidal cell layers. Prolonged (24 hours) electricalstimulation of the perforant path fibers in vivo produceshistopathological changes in the hippocampal CA1 and CA3 pyramidalneurons similar to those elicited by EAAs (Meldrun, B. S., andCorsellis, J. A. N., In “Greenfield's Neuropathology”, 4th Edn., J. H.Adams, et al., Ed., 1984, pp 921-950; Sloviter, R. S., Brain Res. Bull.10, 675-697, 1983; Sloviter, R. S., Science, 73, 1987). The increasedactivity in excitatory hippocampal pathways is suggested as the causefor the irreversible damages to cells, probably by the release of EAAsin neurotoxic concentrations followed by Ca²⁺ influx through thestimulated NMDA receptor-ion channel complex. The mitochondria inselectively vulnerable hippocampal neurons show massive overloading withCa²⁺ during status epilepticus and after 2 hours of reperfusionfollowing cerebral ischemia (Griffiths. T., Neuroscience, 10, 385-395,1983).

[0043] The compounds of the present invention are useful inpharmaceutical compositions using conventional pharmaceutical carriersor vehicles for administration to humans and animals in unit dosageforms, such as tablets, capsules, pills, powders, granules,suppositories, sterile parenteral solutions or suspensions, sterilenon-parenteral solutions or suspensions, oral solutions or suspensions,oil in water or water in oil emulsions and the like, containing suitablequantities of the active ingredient.

[0044] Compositions for injection, may be prepared in unit dosage formin ampules, or in multidose containers. The injectable compositions maytake such forms as suspensions, solutions, or emulsions in oily oraqueous vehicles, and may contain various formulating agents.Alternatively, the active ingredient may be in powder form forreconstitution at the time of delivery with a suitable vehicle, such assterile water. In injectable compositions, the carrier is typicallycomprised of sterile water, saline or another injectable liquid. Also,various buffering agents, preservatives and the like can be included.

[0045] Topical applications may be formulated in carriers such ashydrophobic or hydrophilic bases to form ointments, creams, lotions, inaqueous, oleaginous or alcoholic liquids to form paints or in drydiluents to form powders.

[0046] Oral compositions may take such forms as tablets, capsules, oralsuspensions and oral solutions. The oral compositions may utilizecarriers such as conventional formulating agents, and may includesustained release properties as well as rapid delivery forms.

[0047] The dosage to be administered depends to a large extent upon thecondition and size of the subject being treated, the route and frequencyof administration, and the particular compound selected. Such matters,however, are left to the routine discretion of the physician accordingto principles of treatment well known in the medical arts. Thecompositions of this invention for human delivery per unit dosage,whether liquid or solid, comprise from about 0.01% to as high as about99% of the active compound, the preferred range being from about 10-60%.

[0048] The invention described herein also includes a method of treatinga mammal in need of ischemia treatment comprising administering to saidmammal the claimed composition in an amount effective to treat saidcondition. About 1 to 300 mg/kg of body weight, preferably about 25 to200 mg/kg, one to four times daily is preferred.

[0049] The 5-pyridyl substituted triazoline compounds represented bystructures I, II and III of this invention may be prepared by thereaction of diazomethane with Schiff bases as described in theApplicant's previous patents on triazolines (P. K. Kadaba, U.S. Pat. No.4,511,572, 1985; U.S. Pat. No. 4,689,334, 1987, the disclosures of whichare hereby incorporated by reference), and illustrated in Equation 1.

[0050] where R² is 4-, 3- or 2-pyridyl and R¹ is 3,4- or 3,5-dichloro,p- or m-chloro, p- or m-bromo, p- or m-fluoro, p- or m-trifluoromethyl,p- or m-lower alkyl, p- or m-lower alkoxy or hydrogen.

[0051] In the method of preparation, the reaction between the Schiffbase and diazomethane is carried out by treating the appropriate Schiffbase with a dioxane solution of diazomethane at room temperature, asdescribed previously (P. K. Kadaba, U.S. Pat. No. 4,511,572, 1985; U.S.Pat. No. 4,689,334, 1987).

[0052] The following examples are presented to illustrate the invention,but it is not to be considered as limited thereto. In the examples andthroughout the specifications, parts are by weight unless otherwiseindicated.

EXAMPLE 1

[0053] Preparation of 1-Phenyl-5-(4-,3-, or2-pyridyl)-1,2,3-triazolines:

[0054] To a wet (undried) solution of diazomethane in p-dioxane (0.06mole), contained in an Earlenmeyer flask and kept cold in an ice bath,is added the Schiff base (0.03 mole), and gently swirled until completesolution resulted. The flask is then stoppered with a clean cork, andallowed to stand at room temperature for 2496 hours as necessary. At theend of the reaction, if crystals of the triazoline have appeared, thereaction mixture is filtered, and the filtrate cooled and diluted withwater until a precipitate is obtained. It is filtered, and crystallizedfrom ethanol or acetone or acetone-petroleum ether. The total yield ofpure products ranges from 60-80%.

[0055] The 1,2,3-triazolines that are prepared according to the abovedescribed procedure are all patented (P. K. Kadaba, U.S. Pat. No.4,511,572, 1985; U.S. Pat. No. 4,689,334, 1987) and presented in Table Ialong with their melting points and yields.

[0056] The 5-(2-oxo-1-pyrrolidino)-1,2,3-triazolines represented bystructure IV of this invention, may be prepared by reacting aryl azideswith N-vinylpyrrolidinone as described in the U.S. patent (P. K. Kadaba,U.S. Pat. No. 4,820,721,1989, the disclosure of which is herebyincorporated by reference), and shown in Equation 2.

[0057] where R¹ is as defined above.

[0058] In the method of preparation, the reaction between theN-vinylpyrrolidinone and the phenyl azide is carried out at roomtemperature in ethanol as solvent, and allowed to stand in the dark forseveral weeks, depending on the reactivity of the phenyl azides.Refluxing the reaction mixture eliminates the 5-(2-oxo-1-pyrrolidino)group and yields the 1-phenyl triazole.

[0059] The following examples are presented to illustrate the invention,but it is not to be considered as limited thereto. In the examples andthroughout the specifications, parts are by weight unless otherwiseindicated.

EXAMPLE 2

[0060] Preparation of1-Phenyl-5-(2-oxo-1-pyrrolidino)-Δ²-1.2.3-triazolines

[0061] To the N-vinylpyrrolidinone is added the appropriatelysubstituted phenyl azide, and the reaction mixture is allowed to standin the dark at room temperature, with periodic shaking, for severalweeks, depending on the reactivity of the azide. The reaction isconsidered to be complete when the oily mixture has almost solidified toa crystalline mass. The chunky mass of crystals is triturated with smallportions of ethanol, suction filtered and washed several times withether or an ether-petroleum ether mixture, as the case may be, until allof the unreacted N-vinylpyrrolidinone is removed. The triazolines arecrystallized from acetone or acetone-petroleum ether mixture. The yieldsof the pure compounds range from 45% to 75%.

[0062] The 1-phenyl-5-(2-oxo-1-pyrrolidino)-1,2,3-triazolines preparedaccording to the above procedure are patented (P. K. Kadaba, U.S. Pat.No. 4,820,721, 1989) and are given in Table II along with their meltingpoints and yields.

[0063] The aminoalkylpyridines of this invention, represented bystructures V, VI and VII, may be prepared by the reaction of pyridylalkyl ketones with the appropriate anilines, followed by sodiumborohydride reduction of the resulting ketimines, according to Equation3, following the procedure described in an earlier patent (P. K. Kadaba,U.S. Pat. No. 5,648,369, 1997, the disclosure of which is herebyincorporated by reference).

[0064] In the above equation, R³ is 4-, 3- or 2-pyridyl group, R⁴ ismethyl or ethyl and R¹ is as defined above previously.

[0065] In the method of preparation, the pyridyl alkyl ketone iscondensed with the aniline in refluxing xylene, in the presence ofcommercially available molecular sieves. The imine formed by thisreaction is then reduced by sodium borohydride in ethanol.

[0066] The following examples are presented to illustrate the invention,but it is not to be considered as limited thereto. In the examples andthroughout the specifications, parts are by weight unless otherwiseindicated.

EXAMPLE 3

[0067] Preparation of 1-[N-(Phenyl)-1-(4-, 3-, or 2-pyridyl)]-1 ethyl(or propyl) amine:

[0068] A mixture of the appropriately substituted acetyl or propionylpyridine (0.06 mole) and the appropriately substituted aniline (0.06mole) in xylene (150 ml) is refluxed for 4 hours in the presence ofmolecular sieves (75 g; Davison, grade 514, effective pore size 4A°,8-12 mesh beads). At the end of the reaction, the molecular sieves arefiltered, washed with benzene and the combined filtrates rotaryevaporated to remove xylene. The syrupy residual material iscrystallized from benzene or benzene-petroleum ether mixture to yieldthe pure imines in yields varying from 40% to 60%. The imines that areprepared according to this procedure are given in Table III, along withtheir yields and melting points.

[0069] Sodium Borohydride Reduction of Imines:

[0070] To a solution of the imine (0.03 mol) in ethanol (100 ml), isadded finely powdered sodium borohydride (0.15 mol) and the reactionmixture refluxed with magnetic stirring for 2-4 hours.

[0071] The reaction mixture is then cooled in an ice bath and the excesssodium borohydride is destroyed by slow addition of dilute hydrochloricacid (1:1 mixture), until the reaction mixture is acidic and no morehydrogen evolution is noticed. The white inorganic solids thatprecipitate are dissolved by addition of water and the solution thenmade basic with sodium hydroxide. It is then cooled in the refrigeratorfor 1-2 days, when the 1-[N-(phenyl)]-1-(pyridyl)-1-alkylamines appearas white to beige colored solids. They are filtered, washed well withwater until the filtrate is neutral, and recrystallized from a mixtureof acetone-petroleum ether or tertiary-butyl methyl ether and petroleumether. In Table IV, melting points and yields are given for all the1-[N-(phenyl)]-1-(pyridyl)-1-ethyl-(or propyl) amine compounds that areprepared, including a number of new compounds, not known before.

EXAMPLE 4

[0072] The 1,2,3-triazolines and the AAP compounds of this invention areeffective by the intraperitoneal, intravenous, and oral routes ofadministration. These compounds are effective antiischemic/antistrokeagents that are useful in the treatment of cerebral ischemia in humans,both focal and global, resulting from stroke.

[0073] The potency of these compounds range from those which are veryhighly potent to those of good medium potency, with no accompanyingtoxicity, in both the gerbil model of global ischemia and the rat modelof focal ischemia.

[0074] There is a definite need for more effective, clinically usefuldrugs in the management of stroke. Lipophilicity and penetration of theblood brain barrier are important factors to be taken into considerationwhen designing antistroke drugs, because systemic drug administration asquickly as possible after an episode of stroke is essential to preventthe onset and spread of neuronal injury. The highly lipophilictriazolines and AAPs can enter the brain in less than 15 minutes afterintraperitoneal administration, and reduce or prevent excitotoxicity asearly as possible in the ischemic brain. Furthermore, their oralactivity, especially that of the AAPs, makes them suitable candidatesfor delayed post treatment of the stroke victims, without evincing unduemotor toxicity.

[0075] Evaluation of Antiischemic Activity:

[0076] A series of triazolines with different 5-substituents and thecorresponding metabolite analogue compounds, the AAPs, of thisinvention, has been evaluated for antiischemic activity by theintraperitoneal route using two reliable paradigms of brain injury instroke, the bilateral carotid occlusion model in the gerbil and themiddle cerebral artery occlusion (MCAO) model in the rat. These twoexperimental procedures will indicate the potential of theanticonvulsant triazolines and AAPs, for reducing or preventing neuronaldamage following cerebral ischemia.

[0077] The compounds are initially tested in the gerbil model of globalischemia, to establish the presence or absence of neuroprotective effectin the drug, when administered intraperitoneally as a pretreatmentcompound. Compound's ability to protect neurons from reperfusion injuryin the gerbil is carried out using histopathological and behavioralassessments. The more active compounds are then advanced for furtherevaluation in the rat MCAO model of reversible focal cerebral ischemiaafter ip administration. This model is a clinically relevant model, asit mimics stroke in humans. Compound evaluation in the rat modelconsists of behavioral and histopathological studies and focused onhippocampal damage in the CA1 and CA3 pyramidal neurons.

EXAMPLE 5

[0078] The Bilateral Carotid Occlusion Model of Global Ischemia in theGerbil to Study the Effects of Pretreatment Doses.

[0079] Male gerbils (50-60 gm, Tumblebrook Farm, West Brookfield, Mass.)are housed in groups of three for at least one week prior toinstrumentation. Following surgery, the gerbils are singly housed inorder to avoid the possible accidental induction of ischemia by cagemates. Food and water are available ad libitum in the home cage. Allgerbils are maintained under a 12 hr light/dark cycle.

[0080] Transient ischemia is produced by occluding both common carotidsusing surgically placed occluders (Chandler, M. J., et al., J.Pharmacol. Meth 14, 137-146, 1985). A ventral midline incision is madein the neck of gerbils anesthetized with pentobarbital (40 mg/kg).Common carotids are exposed and separated from the vagosympathetic nervetrunk. A loop of unwaxed dental floss (Johnson and Johnson) is placedaround each carotid. The ends of the floss are each passed through oneof the lumens of a double lumen catheter (Dural Plastics andEngineering, Dural, NSW, Australia). The catheter and dental floss arepassed through the dorsal musculature and exited at the dorsal surfaceof the neck. The catheter is fixed in position, directly above thecarotid artery, using cyanoacrylate adhesive at the exit site. Thedental floss length is marked in order to assure that the animal doesnot occlude the carotid during daily cleaning and exploratory activity.The ventral incision is closed with 9 mm wound clips. After 48 hoursfollowing instrumentation, ischemia is produced by gently pulling thelooped dental floss until the artery is occluded. Occlusion of theartery is associated with depression of spontaneous motor activity, lossof consciousness, ptosis and a change in breathing pattern. Completeinterruption of blood flow occurs under these conditions. The occlusionis maintained for 5 minutes, and then the dental floss is removed toallow complete reperfusion, when these symptoms reverse. Afterreperfusion, the catheter is trimmed flush with the surface of the neck.

[0081] During the 5 minutes of ischemia and for a minimum of 2 hoursafter reversal of carotid occlusion, rectal and cranial temperature willbe maintained at 3637° in all animals. The rectal and cranialtemperatures will be adjusted to the desired levels by heating orcooling from a blanket-jacketed water bath, as described previously(Busto, R., et al., Stroke, 20, 904-910, 1989; Campos-Gonzales, R., andKindy, M. S., J. Neurochem., 59, 1955-1958, 1992). All gerbils will bemonitored for seizures that may occur during postischemic reperfusion.Any gerbil demonstrating motor activity that could be associated withseizures is discarded.

[0082] Gerbils (n=6) are pretreated intraperitoneally, 30 minutes priorto the initiation of carotid occlusion, with an appropriate dose of thetriazoline or AAP compound. If the highest dose of any of the testcompounds caused undue toxicity or mortality, then a lower dose of drugis used (eg. 100, 150, and 200 mg/kg). All animals are tested forpostischemic locomotor activity using a computer-controlled monitoringequipment. A brief description of the equipment and the technique are asfollows. The locomotor activity arena consists of a walled, cylindricaldrum of 2-foot diameter that is equipped with two orthogonally placedphotocell detector systems. Interruption of each of the photocelldetector beams will define an activity count. All activity counts willbe recorded automatically by an IBM computer system. Each gerbil will betested 24 hours after reversal of carotid occlusion or sham-ischemia.

[0083] After locomotor activity testing, gerbils are evaluated fordifferences in patrolling behavior using a eight-arm radial maze. Inthis procedure, animals are placed into the center start chamber of themaze, the barrier removed and the amount of time and the number oftimes, the animals make an error recorded, prior to completion ofexploration in all 8 arms of the maze. An error is defined as therevisiting of an arm by entering to the extent of the entire bodywithout including tail by the animal. If the animal persevers or failsto leave the arm for longer than fifteen minutes, the session isterminated. In all the evaluations reported here, animals never exceededthe fifteen minute cut-off point and all eight-arms were successfullyexplored with differing degrees of errors. In the control population ofthe animals, the number of errors and exploration of the maze with noprior experience (naive) was approximately 5 errors. Data are expressedas the mean (+/−S.E) for groups of 6 gerbils. Following 5 minutes ofbilateral carotid occlusion and testing at 24 hours, gerbils make anaverage number of errors of 28. When animals are pretreated with drug,there is a dose-related decrease in the number of errors made (TableIV). The threshold for protection in the maze test is lower than thatseen in the locomotor activity test. While not significantly differentfrom saline, a dose of 10 mg/kg slightly reduces the number of errors inpost ischemic gerbils.

[0084] All animals will then be subjected to seven day post-reperfusionhistopathological assessment after being re-anesthetized with 60 mg/kgof pentobarbital. Histopathology is determined using frozen sectionsfixed on treated slides and stained with hematoxylin-eosin for cell bodycounting. Changes in neuronal nuclei are determined for the dorsalhippocampus and for the CA3 region as comparison. Histopathologicalevaluation of gerbil brains seven days after 5 minutes of ischemiademonstrates, the expected loss of CA1 hippocampus pyramidal cells(Kirino, T., Brain Res., 239, 57, 1982).

[0085] Table V presents the results of testing the compounds in thegerbil model. This table identifies the specific compounds tested bytheir chemical name, and provides the test model, the route ofadministration, and the antiischemic activity as indicated by neuronaldensity and radial maze errors and calculated as percent protectionafforded by the compound, when administered intraperitoneally to thegerbils as a pretreatment dose.

EXAMPLE 6

[0086] MCAO Rat Model of Reversible Focal Cerebral Ischemia:

[0087] Males of a spontaneously hypertensive inbred strain of Wistar rat(SHR) (250-350 gm., purchased from Harlan, Indianapolis, 1N) are usedfor the preparation of this model since they have been found superior toothers in producing consistent infarct volumes and also becausehypertension is a well-documented risk factor in stroke (Brint, S., etal., J. Cereb. Blood Flow Metab., 8, 474-485, 1988). The rats aremaintained under conditions of controlled lighting (12:12 light/darkcycle) and temperature (22° C.) and allowed free access to lab chow andtap water. All experiments are performed during “lights on” hours. Amethod of reversible focal ischemia in the rat is used, similar to theoriginal technique of Brint and colleagues (1988) as modified byAronowski and co-workers (Aronowski, J., et al., Stroke, 25, 2235-2240,(1994). It involves temporary occlusion of the MCA (middle cerebralartery) and ipsilateral CCA (common carotid artery) for two hours, toproduce infarct volumes that are 50% of those observed with permanentCCA-MCA occlusion (Pettigrew, L. C., et al., J. Cereb. Blood FlowMetab., 16, 1189-1202, 1996; Smith-Swintosky, V. L., et al., J. Cereb.Blood Flow Metab., 16, 585-598, 1996).

[0088] Animals are fasted overnight prior to surgical preparation forischeimia. Each rat is anesthetized with 500 mg/kg chloral hydrate forisolation of MCA and CCA. A catheter is inserted into the right femoralartery for sampling of blood and measurement of mean arterial bloodpressure (MABP) on a graphic recorder (Model RS3400, Gould Electronics,Centerville, Ohio), to monitor preischemic and 30 min postischemic bloodglucose levels, blood gases and hematocrits. A second catheter isinserted into the right femoral vein for injection of drug or vehicle.Electroencephalographic (EEG) and electrocardiographic (ECG) activitiesare monitored through subdermal electrodes and displayed on the graphicrecorder. Thermistor probes are inserted into the rectum and temporalismuscles to monitor body and brain temperature, which is maintained at36-37° C. by external warming. The left CCA is isolated through ananterior incision in the neck. A second incision is made between thelateral canthus of the left eye and the ipsilateral external auditorycanal to expose the underlying skull. Under direct visualization with aZeiss operating microscope, the left MCA is exposed through a 2-mmburrhole drilled 2-3 mm rostral to the fusion of the zygomatic arch andthe squamosal bone. The dura is opened with a sharp needle and an alloywire (0.1 mm diameter) is inserted beneath the MCA just superior to theinferior cortical vein. The MCA is elevated from the cortical surfaceand reversibly occluded by compression against the wire. Obstruction ofblood flow in the MCA is confirmed by direct microscopic observation. Abed of saline-soaked cotton is fashioned to keep the MCA moist while itis being occluded. A surgical clip is used to occlude the CCA for thetwo-hour period. Ischemia is reversed by removing the clip from the CCAand withdrawing the wire from beneath the MCA. The scalp and neckincisions are sutured before the rat is returned to its cage and givenfree access to water and chow.

[0089] Drug is administered intraperitoneally before ischemia or duringpostischemic reperfusion. The doses selected are those shown to beeffective in preventing CA1 neuronal loss in pretreated gerbils. Groupsof sham-ischemic (n=10) and ischemic control (n=10) animals are preparedfor comparison to drug-treated SHRs. Other groups of sham-ischemicanimals are pretreated with the most effective dose of each compoundshown to prevent CA1 neuronal loss in gerbils (n=6 in each group).Another group of six SHRs will be pretreated with the same maximallyeffective dose of each neuroprotective compound before the animalsundergo two hours of CCA-MCA occlusion. The post-treatment groups aregiven the same dose immediately after reversal of ischemia, or followingone, three, or six hours of reperfusion (n=6 in each group). All animalswill undergo functional assessment of cognitive performance before beingeuthanized for measurement of infarct volume 24 hours after reversal ofischemia.

[0090] Measurement of Infarct Volume:

[0091] The size of the infarction resulting from two hours of MCAO, isquantified using triphenyltetrazolium chloride (TTC) staining asdescribed by Bederson, J. B., and colleagues (Stroke, 17, 1304-1308,1986). Twenty-four hours following MCAO, rats are re-anesthetized withchloral hydrate (500 mg/kg body weight) and perfused transcardially withheparinized saline. The brains are removed and chilled at −20° C. for 15minutes before being placed in a Rodent Brain Matrix (ASI Instruments).Seven serial one-mm thick coronal sections through the rostral to caudalextent of the infarction are obtained from each brain, beginning two mmfrom the frontal pole (corresponding to approximately 10.2 mm from theintra-aural line). This procedure reproducibly includes the entireinfarction observed in permanent focal ischemia (Smith-Swintosky, V. L.,et al., J. Cereb. Blood Flow Metab., 16, 585-598, 1996). The individualsections are immersed in 2% TTC and incubated at 37° C. for 10 minuteson each surface. The TTC-stained sections are then placed in 10%formalin and kept in darkness at 4° C. for at least 24 hours. Theinfarct area in each section is determined with a computer-assistedimage analysis system, consisting of a Power Macintosh computer (AppleComputer) equipped with a Quick Capture frame grabber card (DataTranslations), Hitachi CCD camera mounted on an Olympus BX40 microscope,and NIH Image Analysis software, v. 1.55. The system is calibratedagainst a Kodak Optical Density Standard. An optical density thresholdis taken from healthy gray matter in the unaffected right cortex andused to create an artificial color image to distinguish betweeninfarcted and normal tissue. The artificial color image and videophotograph of each slice is used to compute the area of the infarct(38.4 pixels/mm), which is expressed as a fraction of the total area inthe left hemisphere. The total volume of the infarction is computed bymultiplying the infarct area in each coronal section by the number ofslices (n=7) and the thickness of each slice (one mm uniformly). Allmeasurements of infarct volume are performed by a single operatorblinded to treatment status. Statistical comparison of the ischemiccontrol animals to multiple groups of treated, ischemic rats will beaccomplished by ANOVA with Dunnett's post hoc test. TABLE I1-(Phenyl)-5-(pyridyl)-Δ²-1,2,3-triazolines Melting Compound Point, ° C.Yield, % (1)  1-(Phenyl)-5-(4-pyridyl)-Δ²-1,2,3-triazoline 160-161 68(2)  1-(p-Chlorophenyl)-5-(4-pyridyl)-Δ²-1,2,3-triazoline 151-152 82(3)  1-(m-Chlorophenyl)-5-(4-pyridyl)-Δ²-1,2,3-triazoline 109-111 80(4)  1-(p-Fluorophenyl)-5-(4-pyridyl)-Δ²-1,2,3-triazoline 139-140 91(5)  1-(m-Fluorophenyl)-5-(4-pyridyl)-Δ²-1,2,3-triazoline (6) 1-(p-Bromophenyl)-5-(4-pyridyl)-Δ²-1,2,3-triazoline 158-160 51 (7) 1-(m-Bromophenyl)-5-(4-pyridyl)-Δ²-1,2,3-triazoline (8) 1-(3,4-Dichlorophenyl)-5-(4-pyridyl)-Δ²-1,2,3-triazoline 171-172 82 (9) 1-(3,5-Dichlorophenyl)-5-(4-pyridyl)-Δ²-1,2,3-triazoline (10)1-(p-Trifluoromethylphenyl)-5-(4-pyridyl)-Δ²-1,2,3- 149-150 58triazoline (11) 1-(m-Trifluoromethylphenyl)-5-(4-pyridyl)-Δ²-1,2,3-68-71 42 triazoline (12)1-(p-Methylphenyl)-5-(4-pyridyl)-Δ²-1,2,3-triazoline 157-158 97 (13)1-(m-Methylphenyl)-5-(4-pyridyl)-Δ²-1,2,3-triazoline (14)1-(p-Methoxyphenyl)-5-(4-pyridyl)-Δ²-1,2,3-triazoline   148-148.5 45(15) 1-(m-Methoxyphenyl)-5-(4-pyridyl)-Δ²-1,2,3-triazoline (16)1-(3,4-Difluorophenyl)-5-(4-pyridyl)-Δ²-1,2,3-triazoline (17)1-(Phenyl)-5-(3-pyridyl)-Δ²-1,2,3-triazoline 113-114 27 (18)1-(m-Chlorophenyl)-5-(3-pyridyl)-Δ²-1,2,3-triazoline 75-77 75 (19)1-(3,5-Dichlorophenyl)-5-(3-pyridyl)-Δ²-1,2,3-triazoline 95-97 70 (20)1-(p-Trifluoromethylphenyl)-5-(3-pyridyl)-Δ²-1,2,3-triazoline 138-140 50(21) 1-(m-Trifluoromethylphenyl)-5-(3-pyridyl)-Δ²-1,2,3-triazoline 72-7440 (22) 1-(p-Fluorophenyl)-5-(3-pyridyl)-Δ²-1,2,3-triazoline 104-106 60(23) 1-(m-Fluorophenyl)-5-(3-pyridyl)-Δ²-1,2,3-triazoline (24)1-(m-Bromophenyl)-5-(3-pyridyl)-Δ²-1,2,3-triazoline 75-77 65 (25)1-(m-Methylphenyl)-5-(3-pyridyl)-Δ²-1,2,3-triazoline (26)1-(m-Methoxyphenyl)-5-(3-pyridyl)-Δ²-1,2,3-triazoline (27)1-(p-Chlorophenyl)-5-(2-pyridyl)-Δ²-1,2,3-triazoline 138 80 (28)1-(Phenyl)-5-(2-pyridyl)-Δ²-1,2,3-triazoline 83-85 53 (29)1-(p-Trifluoromethylphenyl)-5-(2-pyridyl)-Δ²-1,2,3-triazoline

[0092] TABLE II 1-(Phenyl)-5-(2-oxo-1-pyrrolidino)-Δ²-1,2,3-triazolinesMelting Point, ° C. Yield % (1) 1-(Phenyl)-5-(2-oxo-1-pyrrolidino)-Δ²-1,2,3-triazoline 118.5-121   46(2)  1-(p-Chlorophenyl)-5-(2-oxo-1-pyrrolidino)-Δ²-1,2,3-triazoline126-128 62 (3)  1-(3,4-Dichlorophenyl)-5-(2-oxo-1-pyrrolidino)-Δ²-1,2,3-  133-133.5 70 triazoline (4) 1-(p-Bromophenyl)-5-(2-oxo-1-pyrrolidino)-Δ²-1,2,3-triazoline  129-131.5 60 (5) 1-(p-Fluorophenyl)-5-(2-oxo-1-pyrrolidino)-Δ²-1,2,3-triazoline 111-11421 (6)  1-(p-Trifluoromethylphenyl)-5-(2-oxo-1-pyrrolidino)-Δ²-1,2,3-130-133 66 triazoline (7) 1-(m-Trifluoromethylphenyl)-5-(2-oxo-1-pyrrolidino)-Δ²-1,2,3- 102-105 60triazoline (8)  1-(p-Methylphenyl)-5-(2-oxo-1-pyrrolidino)-Δ²-1,2,3-110.5-113   55 triazoline (9) 1-(p-Methoxyphenyl)-5-(2-oxo-1-pyrrolidino)-Δ²-1,2,3- 122-125 62triazoline (10) 1-(3,5-Dichlorophenyl)-5-(2-oxo-1-pyrrolidino)-Δ²-1,2,3-triazoline (11)1-(m-Chlorophenyl)-5-(2-oxo-1-pyrrolidino)-Δ²-1,2,3-triazoline

[0093] TABLE III Aminoalkylpyridine (AAP) Compounds (Methyl, Ethyl orPropylamine Derivatives) Melting Compound Point, ° C. Yield, % (2) N-(p-Chlorophenyl)-4-pyridylmethylamine 91-94 26 (3) N-(3,4-Dichlorophenyl)-4-pyridylmethylamine   99-101.5 31 (4) N-(3,5-Dichlorophenyl)-4-pyridylmethylamine (5) N-(m-Chlorophenyl)-4-pyridylmethylamine 82-84 18 (6) N-(p-Bromophenyl)-4-pyridylmethylamine   92-94.5 32 (7) N-(m-Bromophenyl)-4-pyridylmethylamine (8) N-(p-Fluorophenyl)-4-pyridylmethylamine 67-70 33 (9) N-(m-Fluorophenyl)-4-pyridylmethylamine (10)N-(p-Methylphenyl)-4-pyridylmethylamine 71-73 38 (11)N-(p-Methoxyphenyl)-4-pyridylmethylamine 74.5-76   33 (12)1-[N-(p-Methylphenyl)]-1-(4-pyridyl)-1-ethylamine   93-95.5 72 (13)1-[N-(p-Methoxyphenyl)]-1-(4-pyridyl)-1-ethylamine 74.5-76   70 (14)1-[N-(Phenyl)]-1-(4-pyridyl)-1-ethylamine 126-128 60 (15)1-[N-(m-Chlorophenyl)]-1-(4-pyridyl)-1-ethylamine   157-159.5 71 (16)1-[N-(3,4-Dichlorophenyl)]-1-(4-pyridyl)-1-ethylamine 153.5-155   54.3(17) 1-[N-(3,5-Dichlorophenyl)]-1-(4-pyridyl)-1-ethylamine   150-152.574 (18) 1-[N-(p-Bromophenyl)]-1-(4-pyridyl)-1-ethylamine   107-108.5 62(19) 1-[N-(m-Bromophenyl)]-1-(4-pyridyl)-1-ethylamine (20)1-[N-(p-Fluorophenyl)]-1-(4-pyridyl)-1-ethylamine 85-87 60 (21)1-[N-(m-Fluorophenyl)]-1-(4-pyridyl)-1-ethylamine (22)1-[N-(3,4-Difluorophenyl)]-1-(4-pyridyl)-1-ethylamine   87-90.0 72 (23)1-[N-(m-Trifluoromethylphenyl)]-1-(4-pyridyl)-1-ethylamine 149-151 72(24) 1-[N-(Phenyl)]-1-(3-pyridyl)-1-ethylamine 132.5-134   77 (25)1-[N-(m-Chlorophenyl)]-1-(3-pyridyl)-1-ethylamine 120-122 47 (26)1-[N-(p-Fluorophenyl)-1-(3-pyridyl)-1-ethylamine (27)1-[N-(m-Fluorophenyl)]-1-(3-pyridyl)-1-ethylamine (28)1-[N-(p-Bromophenyl)]-1-(3-pyridyl)-1-ethylamine 128.5-130.5 47 (29)1-[N-(m-Bromophenyl)]-1-(3-pyridyl)-1-ethylamine (30)1-[N-(p-Methylphenyl)]-1-(3-pyridyl)-1-ethylamine   112-113.5 62 (31)1-[N-(p-Methoxyphenyl)]-1-(3-pyridyl)-1-ethylamine   73-74.5 6.3 (32)1-[N-(3,4-Dichlorophenyl)]-1-(3-pyridyl)-1-ethylamine   127-128.5 78(33) 1-[N-(3,5-Dichlorophenyl)]-1-(3-pyridyl)-1-ethylamine (34)1-[N-(Phenyl)]-1-(4-pyridyl)-1-propylamine 75-78 82 (35)1-[N-(p-Chlorophenyl)]-1-(4-pyridyl)-1-propylamine 133-135 84 (36)1-[N-(m-Chlorophenyl)]-1-(4-pyridyl)-1-propylamine 127.5-129.5 54 (37)1-[N-(p-Bromophenyl)]-1-(4-pyridyl)-1-propylamine   128-130.5 74.5 (38)1-[N-(m-Bromophenyl)]-1-(4-pyridyl)-1-propylamine (39)1-[N-(p-Fluorophenyl)]-1-(4-pyridyl)-1-propylamine 94.5-97   45.6 (40)1-[N-(m-Fluorophenyl)]-1-(4-pyridyl)-1-propylamine (41)1-[N-(3,4-Difluorophenyl)]-1-(4-pyridyl)-1-propylamine   104-106.5 40(42) 1-[N-(3,5-Difluorophenyl)]-1-(4-pyridyl)-1-propylamine (43)1-[N-(p-Methoxyphenyl)]-1-(4-pyridyl)-1-propylamine 86-88 62 (44)1-[N-(p-Methylphenyl)]-1-(4-pyridyl)-1-propylamine   117-119.5 74 (45)1-[N-(m-Methoxyphenyl)]-1-(4-pyridyl)-1-propylamine (46)1-[N-(m-Methylphenyl)]-1-(4-pyridyl)-1-propylamine (47)1-[N-(3,4-Dichlorophenyl)]-1-(4-pyridyl)-1-propylamine 154-156 31 (48)1-[N-(3,5-Dichlorophenyl)]-1-(4-pyridyl)-1-propylamine (49)1-[N-(Phenyl)]-1-(3-pyridyl)-1-propylamine 90-92 39 (50)1-[N-(p-Chlorophenyl)]-1-(3-pyridyl)-1-propylamine (51)1-[N-(m-Chlorophenyl)]-1-(3-pyridyl)-1-propylamine (52)1-[N-(p-Bromophenyl)]-1-(3-pyridyl)-1-propylamine (53)1-[N-(m-Bromophenyl)]-1-(3-pyridyl)-1-propylamine (54)1-[N-(p-Fluorophenyl)]-1-(3-pyridyl)-1-propylamine (55)1-[N-(m-Fluorophenyl)]-1-(3-pyridyl)-1-propylamine (56)1-[N-(3,4-Difluorophenyl)]-1-(3-pyridyl)-1-propylamine (57)1-[N-(3,5-Difluorophenyl)]-1-(3-pyridyl)-1-propylamine (58)1-[N-(p-Methylphenyl)]-1-(3-pyridyl)-1-propylamine 100-104 32 (59)1-[N-(m-Methylphenyl)-1-(3-pyridyl)]-1-propylamine (60)1-[N-(p-Methoxyphenyl)]-1-(3-pyridyl)-1-propylamine 94.5-96   74 (61)1-[N-(m-Methoxyphenyl)]-1-(3-pyridyl)-1-propylamine (62)1-[N-(3,4-Dichlorophenyl)]-1-(3-pyridyl)-1-propylamine (63)1-[N-(3,5-Dichlorophenyl)]-1-(3-pyridyl)-1-propylamine (64)1-[N-(Phenyl)]-1-(phenyl)-1-(4-pyridyl)methylamine 91.5-94   48 (65)1-[N-(p-Methoxyphenyl)]-1-(phenyl)-1-(4-pyridyl)- 112-115 96.7methylamine (66) 1-[N-(m-Methoxyphenyl)]-1-(phenyl)-1-(4-pyridyl)-121.5-123   98 methylamine (67)1-[N-(p-Chlorophenyl)]-1-(phenyl)-1-(4-pyridyl)- 135-137 71 methylamine(68) 1-[N-(m-Chlorophenyl)]-1-(phenyl)-1-(4-pyridyl)- 104-106 49methylamine (69) 1-[N-(p-Methylphenyl)]-1-(phenyl)-1-(4-pyridyl)-  134-135.5 60 methylamine (70)1-[N-3,5-Dichlorophenyl)]-1-(phenyl)-1-(4-pyridyl)- Sublimes 56methylamine (71)1-[N-(m-Trifluoromethylphenyl)]-1-(phenyl)-1-(4-pyridyl)-   123-125.5 70methylamine (72) 1-[N-(p-Bromophenyl)]-1-(phenyl)-1-(4-pyridyl)-methylamine (73) 1-[N-(p-Dimethylaminophenyl)]-1-(phenyl)-1-(4-pyridyl)-149-151 63 methylamine (74)1-[N-(3,4-Dichlorophenyl)]-1-(phenyl)-1-(4-pyridyl)-   130-132.5methylamine (75) 1-[N-(p-Chlorophenyl)]-1-(phenyl)-1-(3-pyridyl)- 85-8758 methylamine (76) 1-[N-(m-Chlorophenyl)]-1-(phenyl)-1-(3-pyridyl)-77-80 methylamine (77) 1-[N-(p-Methylphenyl)]-1-(phenyl)-1-(3-pyridyl)-89.5-92.5 50 methylamine (78)1-[N-(p-Methoxyphenyl)]-1-(phenyl)-1-(3-pyridyl)- 114-116 68.5methylamine (79) 1-[N-(Phenyl)]-1-(phenyl)-1-(3-pyridyl)methylamine113.5-115.5 66.8 (80)1-[N-(3,4-Dichlorophenyl)]-1-(phenyl)-1-(3-pyridyl)- 108.5-111   48methylamine (81) 1-[N-(p-Bromophenyl)]-1-(phenyl)-1-(3-pyridyl)-114.5-17.5  22 methylamine (82)1-[N-(m-Trifluoromethylphenyl)]-1-(phenyl)-1-(3-pyridyl)-   81-83.5methylamine (83) 1-[N-(3,5-Dichlorophenyl)]-1-(phenyl)-1-(3-pyridyl)-93-95 17 methylamine (84)1-[N-(p-Chlorophenyl)]-1,1-(bis-2-pyridyl)methylamine   117-119.5

[0094] TABLE IV Results of Testing 1,2,3-Triazolines and AAP Compoundsin the Gerbil Model of Global Ischemia. Degree of Protection in Terms ofNeuronal Cell Count and Number of Radial Arm Maze Errors at ThreeDifferent Drug Concentrations Degree of Protection, % Neuronal RadialCell Count, %^(a) Maze Errors, %^(b) Test Concentrations, mg/kg Compound100 150 200 100 150 200 (1)  1-(Phenyl)-5-(4-pyridyl)- 83.0 91.4 96.528.9 31.6 27.4 Δ²-1,2,3-triazoline (2)  1-(p-Chlorophenyl)-5-(4- 65.382.2 91.4 44.7 30.8 30.1 pyridyl)-Δ²-1,2,3-triazoline (3) 1-(3,4-Dichlorophenyl)-5- 60.0 74.1 88.5 62.1 — —(4-pyridyl)-Δ²-1,2,3-triazoline (4)  1-(p-Fluorophenyl)-5-(4- 54.9 67.877.3 72.2 58.3 45.9 pyridyl)-Δ²-1,2,3-triazoline (5) 1-(p-Trifluoromethylphenyl)-5- 47.0 46.5 62.5 75.9 — —(4-pyridyl)-Δ²-1,2,3-triazoline (6)  1-(m-Chlorophenyl)-5-(4-pyridyl)-60.1 71.2 87.4 44.7 25.7 21.3 Δ²-1,2,3-triazoline (7) 1-(p-Bromophenyl)-5-(4-pyridyl)- 25.6 39.5 47.9 73.5 61.7 54.2Δ²-1,2,3-triazoline (8)  1-(3,5-Dichlorophenyl)-5- 30.6 41.3 49.8 72.256.6 48.1 (4-pyridyl)-Δ²-1,2,3-triazoline (9) 1-(p-Chlorophenyl)-5-(3-pyridyl)- 47.9 53.7 59.7 58.7 52.3 45.3Δ²-1,2,3-triazoline (10) 1-(m-Chlorophenyl)-5-(3-pyridyl)- 46.8 47.362.8 60.3 59.0 45.7 Δ²-1,2,3-triazoline (11) 1-(Phenyl)-5-(3-pyridyl)-49.5 55.6 61.0 57.0 52.0 44.3 Δ²-1,2,3-triazoline (12)1-(p-Chlorophenyl)-5- 45.6 36.9 63.5 60.7 58.3 42.7(2-pyridyl)-Δ²-1,2,3-triazoline (13) 1-(p-Bromophenyl)-5-(2-pyridyl)-47.6 47.2 62.5 62.7 60.0 39.7 Δ²-1,2,3-triazoline (14)1-(Phenyl)-5-(2-oxo-1-pyrrolidino)- 22.0 29.9 38.5 82.7 70.2 60.7Δ²-1,2,3-triazoline (15) 1-(p-Chlorophenyl)-5-(2-oxo-1- 29.9 33.9 45.271.9 57.6 54.9 pyrrolidino)-Δ²-1,2,3-triazoline (16)1-(p-Trifluoromethylphenyl)- 534.2 52.8 66.3 67.4 48.8 34.9(2-oxo-1-pyrrolidino)- Δ²-1,2,3-triazoline (17)1-(m-Trifluoromethylphenyl)- 25.8 38.2 45.8 76.3 63.4 52.25-(2-oxo-1-pyrrolidino)- Δ²-1,2,3-triazoline (18) 1-(p-Bromophenyl)-5-6.4 17.2 21.4 82.2 76.2 74.1 (2-oxo-1-pyrrolidino)- Δ²-1,2,3-triazoline(19) 1-(p-Fluorophenyl)-5- 5.5 16.2 15.4 97.2 76.6 75.9(2-oxo-1-pyrrolidino)- Δ²-1,2,3-triazoline (20)1-(3,4-Dichlorophenyl)-5- 8.1 17.2 18.0 90.9 78.3 80.8(2-oxo-1-pyrrolidino)- Δ²-1,2,3-triazoline (21)1-(3,4-Dichlorophenyl)-5- 8.7 15.8 22.8 89.9 83.6 78.0[N-methyl)-N-acetamide] (22) 1-[N-(p-Chlorophenyl)]-1- 0 6.6 14.5 10088.5 82.4 (4-pyridyl)-1-ethylamine) (No effect) (No effect) (23)1-[N-(p-Bromophenyl)]-1- 0 15.6 28.1 100 81.2 71.3(4-pyridyl)-1-ethylamine) (no effect) (no effect) (24)1-[N-(3,4,-Dichlorophenyl)]-1- 26.4 32.9 45.2 74.7 66.3 65.1(4-pyridyl)-1-ethylamine) (25) 1-[N-(3-Chlorophenyl)]-1- 29.6 39.6 38.982.6 77.6 82.2 (4-pyridyl)-1-ethylamine) (26)1-[N-(3,5,-Dichlorophenyl)]-1- 29.7 32.7 44.1 87.1 84.5 72.7(4-pyridyl)-1-ethylamine) (27) 1-[N-(3-Trifluoromethylphenyl)]- 15.114.6 11.7 103.8 109.1 111.0 1-(4-pyridyl)-1-ethylamine) (compound has noprotective effect) (28) 1-[N-(p-methylphenyl)]-1- 20.0 30.3 38.7 98.189.4 79.5 (4-pyridyl)-1-ethylamine) (29) 1-[N-(p-Chlorophenyl)]-1- 32.036.2 40.5 84.5 83.3 76.9 (3-pyridyl)-1-ethylamine) (30)1-[N-(3,4-dichlorophenyl)]-1- 33.5 41.6 42.9 80.3 74.6 73.5(3-pyridyl)-1-ethylamine) (31) 1-[N-(p-Bromophenyl)]-1- 35.7 19.7 6 81.8101.1 114.0 (3-pyridyl)-1-ethylamine) (32) (+)1-[N-(p-Chlorophenyl)]-1-10.7 14.8 19.1 98.6 92.6 91.2 (4-pyridyl)-1-1 ethylamine) (33)(−)1-[N-(p-Chlorophenyl)]-1- 7.6 15.0 16.5 97.5 81.1 79.0(4-pyridyl)-1-ethylamine)

[0095] TABLE V Results of Testing Δ²-1,2,3-Triazolines in the Rat Modelof Focal Ischemia. Degree of Protection in Terms of Reduction in InfarctVolume; Ip Injection 30 min Prior to Ischemia, at 100, 150 and 200 mg/kgDose Reduction in Infarct Volume, % Test Concentrations of Drug,Dissolved in 0.5% Carboxymethyl Cellulose, mg/kg Compound 100 150 200(1) 1-(Phenyl)-5-(4-pyridyl)- 53.8 33.3 15.2 Δ²-1,2,3-triazoline (2)1-(p-Chlorophenyl)-5- 16.9 — — (4-pyridyl)-Δ²-1,2,3-triazoline (3)1-(p-Fluorophenyl)-5- 0 — — (4-pyridyl)-Δ²-1,2,3-triazoline (Noreduction in infarct volume)

[0096] The invention has been described herein with reference to certainpreferred embodiments. However, as obvious variations thereon willbecome apparent to those of skill in the art, the invention is notconsidered to be limited thereto. TABLE VI Results of TestingΔ²-1,2,3-Triazolines in the Rat Model of Focal Ischemia. Degree ofProtection in Terms of Reduction in Infarct Volume; Post-Ischemic IpInjection of Drug, Three Times, at the Beginning, then 1 hr. and 2 hrs.of Reperfusion. Ischemic Controls Treated 3 Times with Vehicle Reductionin Infarct Volume When Drug is Administered Ip Compound Three Times,Postischemic, % (1) 1-(p-Fluorophenyl)-5- 30(4-pyridyl)-Δ²-1,2,3-triazoline (25 mg/kg × 3) (2)1-(3,4-Dichlorophenyl)- 34 5-(4-pyridyl)-Δ²-1,2,3-triazoline (50 mg/kg ×3)

What is claimed is:
 1. A potent non-neurotoxic antiischemic composition,highly effective by the intraperitoneal route of administration, in thetreatment of both global and focal ischemia, and comprising as theactive ingredient, an effective amount of an antiischemicΔ²-1,2,3-triazoline compound, selected from the group consisting ofthose of the formulae,

wherein R² is 4-pyridyl, 3-pyridyl, or 2-pyridyl and R¹ is 3,4- or3,5-dichloro, p- or m-chloro, p- or m-bromo, p- or m-fluoro, p- orm-trifluoromethyl, p- or m-lower alkyl, p- or m-lower alkoxy orhydrogen, and a pharmaceutical carrier.
 2. A composition according toclaim 1 wherein R is 4-pyridyl and R¹ is hydrogen.
 3. A compositionaccording to claim 1 wherein R² is 4-pyridyl and R¹ is p-chloro.
 4. Acomposition according to claim 1 wherein R² is 4-pyridyl and R¹ is3,4-dichloro.
 5. A composition according to claim 1 wherein R² is4-pyridyl and R¹ is p-fluoro.
 6. A composition according to claim 1wherein R² is 4-pyridyl and R¹ is p-trifluoromethyl.
 7. A compositionaccording to claim 1 wherein R² is 4-pyridyl and R¹ is m-chloro.
 8. Acomposition according to claim 1 wherein R is 4-pyridyl and R¹ isp-bromo.
 9. A composition according to claim 1 wherein R² is 4-pyridyland R¹ is 3,5-dichloro.
 10. A composition according to claim 1 whereinR² is 3-pyridyl and R¹ is m-chloro.
 11. A composition according to claim1 wherein R² is 3-pyridyl and R¹ is p-chloro.
 12. A compositionaccording to claim 1 wherein R² is 3-pyridyl and R¹ is hydrogen.
 13. Acomposition according to claim 1 wherein R² is 2-pyridyl and R¹ isp-bromo.
 14. A composition according to claim 1 wherein R is 2-pyridyland R¹ is p-chloro.
 15. A non-neurotoxic antiischemic composition,effective by the intraperitoneal route of administration in thetreatment of both global and focal ischemia, and comprising as theactive ingredient an effective amount of an antiischemic triazolinecompound, selected from the 2-oxo-1-pyrrolidino-Δ²-1,2,3-triazolinegroup consisting of those of the formulae,

wherein R¹ is 3,4- or 3,5-dichloro, p- or m-chloro, p- or m-bromo, p- orm-fluoro, p- or m-trifluoromethyl, p- or m-lower alkyl, p- or m-loweralkoxy or hydrogen and a pharmaceutical carrier.
 16. A compositionaccording to claim 15 wherein R¹ is p-chloro, p-bromo or p-fluoro.
 17. Acomposition according to claim 15 wherein R¹ is p-trifluoromethyl orm-trifluoromethyl.
 18. A composition according to claim 15 wherein R¹ is3,4-dichloro or 3,5-dichloro.
 19. A composition according to claim 15wherein R¹ is hydrogen.
 20. A 2-oxo-1-pyrrolidino-Δ²-1,2,3-triazolinecompound of the following formulae,

wherein R¹ is 3,4- or 3,5-dichloro, p- or m-chloro, p- or m-bromo, p- orm-fluoro, p- or m-trifluoromethyl, p- or m-lower alkyl, p- or m-loweralkoxy or hydrogen.
 21. A 2-oxo-1-pyrrolidino-Δ²-1,2,3-triazolinecompound according to claim 20 wherein R¹ is p-bromo or p-fluoro.
 22. A2-oxo-1-pyrrolidino-Δ²1,2,3-triazoline compound according to claim 20wherein R¹ is m-chloro or 3,5-dichloro.
 23. A 4-pyridyl methylaminecompound of the following formulae,

wherein R¹ is p- or m-chloro, 3,4- or 3,5-dichloro, p- or m-bromo, p- orm-fluoro, p -methyl or methoxyl.
 24. A 1-(4-pyridyl)-1-ethylaminecompound of the following formulae,

wherein R¹ is 3,4- or 3,5-dichloro, 3,4- or 3,5-difluoro, p- orm-chloro, p- or m-bromo, p- or m-fluoro, p- or m-trifluoromethyl, p- orm-lower alkyl, p- or m-lower alkoxy or hydrogen.
 25. A1-(4-pyridyl)-1-ethylamine compound according to claim 24 wherein R¹ is3,5-dichloro.
 26. A 1-(4-pyridyl)-1-ethylamine compound according toclaim 24 wherein R¹ is m-bromo, m-fluoro, m-trifluoromethyl, or3,4-difluoro.
 27. A 1-(3-pyridyl)-1-ethylamine compound of the followingformulae,

wherein R¹ is 3,4- or 3,5-dichloro, p- or m-chloro, p- or m-bromo, p- orm-fluoro, p- or m-trifluoromethyl, p- or m-lower alkyl, p- or m-loweralkoxy or hydrogen.
 28. A 1-(3-pyridyl)-1-ethylamine compound accordingto claim 27 wherein R¹ is p-chloro, p-bromo or 3,4-dichloro.
 29. A1-(4-pyridyl)-1-propylamine compound of the following formulae,

wherein R¹ is 3,4- or 3,5-dichloro, 3,4- or 3,5-difluoro, p- orm-chloro, p- or m-bromo, p- or m-fluoro, p- or m-trifluoromethyl, p- orm-lower alkyl, p- or m-lower alkoxy or hydrogen.
 30. A1-(3-pyridyl)-1-propylamine compound of the following formulae,

wherein R¹ is 3,4- or 3,5-dichloro, 3,4- or 3,5-difluoro, p- orm-chloro, p- or m-bromo, p- or m-fluoro, p- or m-trifluoromethyl, p- orm-lower alkyl, p- or m-lower alkoxy or hydrogen.
 31. Aα-phenyl-α-(4-pyridyl)methylamine compound of the following formulae,

wherein R¹ is 3,4- or 3,5-dichloro, p- or m-chloro, p- or m-bromo, p- orm-fluoro, m-trifluoromethyl, p-dimethylamino, p- or m-lower alkyl, p- orm-lower alkoxy or hydrogen.
 32. A α-phenyl-α-(3-pyridyl)methylaminecompound of the following formulae,

wherein R¹ is 3,4- or 3,5-dichloro, p- or m-chloro, p-bromo,m-trifluoromethyl, p-methyl, p-methoxy or hydrogen.
 33. Aα,α-bis-(2-pyridyl)methylamine compound of the following formula,


34. A non-neurotoxic antiischemic composition, effective by theintrapentoneal route of administration in the treatment of globalischemia and comprising as the active ingredient, an effective amount ofan antiischemic compound selected from the group consisting of those ofthe formulae,

wherein R² is 4-pyridyl or 3-pyridyl, R³ is hydrogen, methyl or ethyl,and R¹ is 3, 4- or 3,5-dichloro, 3,4- or 3,5-difluoro, p- or m-chloro,p- or m-bromo, p- or m-fluoro, p- or m-trifluoromethyl, p- or m-loweralkyl, p- or m-lower alkoxy or hydrogen, and a pharmaceutical carrier.35. A composition according to claim 34 wherein R² is 4-pyridyl, R³ ishydrogen, methyl or ethyl, and R¹ is 3,4- or 3,5-dichloro.
 36. Acomposition according to claim 34 wherein R² is 3-pyridyl, R³ ishydrogen, methyl or ethyl, and R¹ is p-chloro, p-bromo, or 3,4-dichloro.37. A composition consisting of an effective amount of an excitatoryamino acid inhibitor (glutamate inhibitor) compound according to claim1, claim 15 and claim 34 to yield an antiischemic composition effectiveagainst global and focal ischeria.
 38. A composition according to claim1, claim 15, claim 34 and claim 37, wherein a sufficient amount of thetriazoline in claims 1, 15 and 20 or aminoalkylpyridine in claims 23,24, 27, 29, 30, 31, 32 and 33 is contained in said composition toprovide a dosage amount ranging from about 25 mg/kg to 200 mg/kg.
 39. Amethod for the treatment of cerebral ischemia resulting from stroke inmammals, including man, which comprises administration thereto of aneffective dosage amount of a triazoline or aminoalkylpyridineantiischemic composition of claim 1, claim 15, claim 34 and claim 37.40. A composition according to claim 34 wherein R² is 3-pyridyl, R³ ishydrogen, methyl or ethyl, and R¹ is p-chloro, p-bromo, or 3,4-dichloro.41. A composition consisting of an effective amount of an excitatoryamino acid inhibitor (glutamate inhibitor) compound according to claim1, claim 15 and claim 34 to yield an antiischemic composition effectiveagainst global and focal ischemia.
 42. A composition according to claim1, claim 15, claim 34 and claim 37, wherein a sufficient amount of thetriazoline in claims 1, 15 and 20 or aminoalkylpyridine in claims 23,24, 27, 29, 30, 31, 32 and 33 is contained in said composition toprovide a dosage amount ranging from about 25 mg/kg to 200 mg/kg.
 43. Amethod for the treatment of cerebral ischemia resulting from stroke inmammals, including man, which comprises administration thereto of aneffective dosage amount of a triazoline or aminoalkylpyridineantiischemic composition of claim 1, claim 15, claim 34 and claim 37.